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NM_000143.4(FH):c.965T>A (p.Val322Asp) AND Hereditary cancer-predisposing syndrome

Germline classification:
Likely pathogenic (1 submission)
Last evaluated:
Jan 26, 2023
Review status:
1 star out of maximum of 4 stars
criteria provided, single submitter
Somatic classification
of clinical impact:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Somatic classification
of oncogenicity:
None
Review status:
(0/4) 0 stars out of maximum of 4 stars
no assertion criteria provided
Record status:
current
Accession:
RCV003219455.2

Allele description [Variation Report for NM_000143.4(FH):c.965T>A (p.Val322Asp)]

NM_000143.4(FH):c.965T>A (p.Val322Asp)

Gene:
FH:fumarate hydratase [Gene - OMIM - HGNC]
Variant type:
single nucleotide variant
Cytogenetic location:
1q43
Genomic location:
Preferred name:
NM_000143.4(FH):c.965T>A (p.Val322Asp)
HGVS:
  • NC_000001.11:g.241504185A>T
  • NG_012338.1:g.20570T>A
  • NM_000143.4:c.965T>AMANE SELECT
  • NP_000134.2:p.Val322Asp
  • NP_000134.2:p.Val322Asp
  • LRG_504t1:c.965T>A
  • LRG_504:g.20570T>A
  • LRG_504p1:p.Val322Asp
  • NC_000001.10:g.241667485A>T
  • NM_000143.3:c.965T>A
Protein change:
V322D
Molecular consequence:
  • NM_000143.4:c.965T>A - missense variant - [Sequence Ontology: SO:0001583]

Condition(s)

Name:
Hereditary cancer-predisposing syndrome
Synonyms:
Neoplastic Syndromes, Hereditary; Tumor predisposition; Cancer predisposition; See all synonyms [MedGen]
Identifiers:
MONDO: MONDO:0015356; MeSH: D009386; MedGen: C0027672

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Assertion and evidence details

Help
Submission AccessionSubmitterReview Status
(Assertion method)		Clinical Significance
(Last evaluated)		OriginMethodCitations
SCV003900968Ambry Genetics
criteria provided, single submitter

(Ambry Variant Classification Scheme 2023)		Likely pathogenic
(Jan 26, 2023) 		germlineclinical testing

PubMed (2)
[See all records that cite these PMIDs]

Citation Link

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Summary from all submissions

EthnicityOriginAffectedIndividualsFamiliesChromosomes testedNumber TestedFamily historyMethod
not providedgermlineunknownnot providednot providednot providednot providednot providedclinical testing

Citations

PubMed

Mutations in the fumarate hydratase gene cause hereditary leiomyomatosis and renal cell cancer in families in North America.

Toro JR, Nickerson ML, Wei MH, Warren MB, Glenn GM, Turner ML, Stewart L, Duray P, Tourre O, Sharma N, Choyke P, Stratton P, Merino M, Walther MM, Linehan WM, Schmidt LS, Zbar B.

Am J Hum Genet. 2003 Jul;73(1):95-106. Epub 2003 May 22.

PubMed [citation]
PMID:
12772087
PMCID:
PMC1180594

Fumarate hydratase mutations and predisposition to cutaneous leiomyomas, uterine leiomyomas and renal cancer.

Alam NA, Olpin S, Leigh IM.

Br J Dermatol. 2005 Jul;153(1):11-7. Review.

PubMed [citation]
PMID:
16029320

Details of each submission

From Ambry Genetics, SCV003900968.2

#EthnicityIndividualsChromosomes TestedFamily HistoryMethodCitations
1not providednot providednot providednot providedclinical testing PubMed (2)

Description

The p.V322D variant (also known as c.965T>A), located in coding exon 7 of the FH gene, results from a T to A substitution at nucleotide position 965. The valine at codon 322 is replaced by aspartic acid, an amino acid with highly dissimilar properties. This alteration has been observed in multiple individuals with a personal and/or family history that is consistent with FH-related disease (Ambry internal data; Toro JR et al. Am J Hum Genet, 2003 Jul;73:95-106; Alam NA et al. Br J Dermatol, 2005 Jul;153:11-7). Of note, this alteration is also designated as T836A and V279D in published literature. Another alteration at the same codon, p.V322G (c.965T>G), has been identified in multiple individuals who meet clinical diagnostic criteria for HLRCC and it has segregated with disease in these families (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.

#SampleMethodObservation
OriginAffectedNumber testedTissuePurposeMethodIndividualsAllele frequencyFamiliesCo-occurrences
1germlineunknownnot providednot providednot providednot providednot providednot providednot provided

Last Updated: May 1, 2024